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Comparative analyses of the in vivo induction and transmission of ?-synuclein pathology in transgenic mice by MSA brain lysate and recombinant ?-synuclein fibrils.


ABSTRACT: ?-synuclein (?S) is the major component of several types of brain pathological inclusions that define neurodegenerative diseases termed synucleinopathies. Central nervous system (CNS) inoculation studies using either in vitro polymerized ?S fibrils or in vivo derived lysates containing ?S aggregates to induce the progressive spread of ?S inclusion pathology in animal disease models have supported the notion that ?S mediated progressive neurodegeneration can occur by a prion-like mechanism. We have previously shown that neonatal brain inoculation with preformed ?S fibrils in hemizygous M20+/- transgenic mice expressing wild type human ?S and to a lesser extent in non-transgenic mice can result in a concentration-dependent progressive induction of CNS ?S pathology. Recent studies using brain lysates from patients with multiple system atrophy (MSA), characterized by ?S inclusion pathology in oligodendrocytes, indicate that these may be uniquely potent at inducing ?S pathology with prion-like strain specificity. We demonstrate here that brain lysates from MSA patients, but not control individuals, can induce ?S pathology following neonatal brain inoculation in transgenic mice expressing A53T human ?S (M83 line), but not in transgenic expressing wild type human ?S (M20 line) or non-transgenic mice within the timeframe of the study design. Further, we show that neuroanatomical and immunohistochemical properties of the pathology induced by MSA brain lysates is very similar to what is produced by the neonatal brain injection of preformed human ?S fibrils in hemizygous M83+/- transgenic mice. Collectively, these findings reinforce the idea that the intrinsic traits of the M83 mouse model dominates over any putative prion-like strain properties of MSA ?S seeds that can induce pathology.

SUBMITTER: Dhillon JS 

PROVIDER: S-EPMC6526622 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Comparative analyses of the in vivo induction and transmission of α-synuclein pathology in transgenic mice by MSA brain lysate and recombinant α-synuclein fibrils.

Dhillon Jess-Karan S JS   Trejo-Lopez Jorge A JA   Riffe Cara C   Levites Yona Y   Sacino Amanda N AN   Borchelt David R DR   Yachnis Anthony Y AY   Giasson Benoit I BI  

Acta neuropathologica communications 20190520 1


α-synuclein (αS) is the major component of several types of brain pathological inclusions that define neurodegenerative diseases termed synucleinopathies. Central nervous system (CNS) inoculation studies using either in vitro polymerized αS fibrils or in vivo derived lysates containing αS aggregates to induce the progressive spread of αS inclusion pathology in animal disease models have supported the notion that αS mediated progressive neurodegeneration can occur by a prion-like mechanism. We ha  ...[more]

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